Polycyclic substituted pyrazole kinase activity inhibitors and use thereof

Abstract

The present invention relates to the field of medicinal chemistry, and in particular relates to 4-(five-membered heterocyclic pyrimidine/pyridine substituted) amino-1H-3-pyrazolecarboxamide derivatives, the preparation method thereof, pharmaceutical compositions containing these compounds and the medicinal use thereof, especially as protein kinase inhibitors for anti-tumor use.

The invention claimed is: 
     
       1. A compound defined by formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or tautomer or solvate thereof or a combination thereof, 
       
       wherein:
 R 1 , R 2  and R 3  each independently represent H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol, alkoxylalkyl, aralkyl, diarylalkyl, aryl or Het; 
 X and Y each independently represent N atom or CH group, wherein the CH group can optionally be substituted by R 4 , and R 4  may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol, alkoxylalkyl, aralkyl, diarylalkyl, aryl or Het; 
 Z and M each independently represent NH, O, S or CH group with the proviso that one of Z and M is NH, O or S, wherein the CH or NH group can each optionally and independently be substituted by R 5 , and R 5  may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol, alkoxylalkyl, aralkyl, diarylalkyl, aryl or Het; 
 A 1  independently represents NH, O, S or alkylene group, wherein the NH or alkylene group can each optionally and independently be substituted by R 6 , and R 6  may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol, alkoxylalkyl, aralkyl, diarylalkyl, aryl or Het; 
 A 2  independently represents alkylene, C(O)NH, C(O), NHC(O), alkylene-C(O), C(O)-alkylene, alkylene-C(O)-alkylene or NHC(O)NH, wherein the above groups can each optionally and independently be substituted by R 7 , and R 7  may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol, alkoxylalkyl, aralkyl, diarylalkyl, aryl or Het; 
 Q 1  is selected from aryl and Het, wherein the aryl or Het can each optionally and independently be substituted by one or more R 8 , and R 8  may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol, alkoxylalkyl, aralkyl, diarylalkyl, aryl or Het; 
 Q 2  is selected from aryl or Het, wherein the aryl or Het can each optionally and independently be substituted by one or more R 9 , and R 9  may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol, alkoxylalkyl, aralkyl, diarylalkyl, aryl and Het; and 
 wherein: 
 the alkyl refers to a linear or branched chain saturated hydrocarbon group having 1-6 carbon atoms, or a cyclic saturated hydrocarbon group having 3-6 carbon atoms, or a cyclic saturated hydrocarbon group having 3-6 carbon atoms which is attached to a linear or branched chain saturated hydrocarbon group having 1-6 carbon atoms; 
 the alkylene refers to a linear or branched chain saturated hydrocarbon group having 1-6 carbon atoms, or a cyclic saturated hydrocarbon group having 3-6 carbon atoms, or a cyclic saturated hydrocarbon group having 3-6 carbon atoms which is attached to a linear or branched chain saturated hydrocarbon group having 1-6 carbon atoms; wherein one hydrogen atom is absent; 
 the alkoxyl refers to a linear or branched chain saturated hydrocarbon group having 1-6 carbon atoms, or a cyclic saturated hydrocarbon group having 3-6 carbon atoms, or a cyclic saturated hydrocarbon group having 3-6 carbon atoms which is attached to a linear or branched chain saturated hydrocarbon group having 1-6 carbon atoms; wherein each carbon atom is optionally substituted by oxygen; 
 the alkylthiol refers to a linear or branched chain saturated hydrocarbon group having 1-6 carbon atoms, or a cyclic saturated hydrocarbon group having 3-6 carbon atoms, or a cyclic saturated hydrocarbon group having 3-6 carbon atoms which is attached to a linear or branched chain saturated hydrocarbon group having 1-6 carbon atoms; wherein each carbon atom is optionally substituted by sulfur; 
 the alkoxylalkyl refers to the alkyl group as defined above, which is attached to the alkoxyl group as defined above; 
 the aryl refers to a carbonic ring selected from phenyl, naphthyl, acenaphthenyl and tetralyl, which may be each optionally substituted by 1, 2 or 3 substituents each independently selected from H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol, alkoxylalkyl, aralkyl, diarylalkyl, aryl and Het; 
 the aralkyl or diarylalkyl refers to the alkyl group as defined above, which is attached to the aryl group as defined above; 
 the Het refers to a monocyclic heterocycle group selected from piperidyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl, or a bicyclic heterocycle group selected from quinolyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuryl, benzothienyl, 2,3-dihydro-1,4-benzodioxinyl and 1,3-benzodioxolyl; wherein the monocyclic or bicyclic heterocycle group is each optionally substituted by 1, 2 or 3 substituents each independently selected from halogen, haloalkyl, hydroxyl, alkyl and alkoxyl; 
 the halogen refers to a substituent selected from fluoro, chloro, bromo and iodo; 
 the haloalkyl refers to a linear or branched chain saturated hydrocarbon group having 1-6 carbon atoms, or a cyclic saturated hydrocarbon group having 3-6 carbon atoms, or a cyclic saturated hydrocarbon group having 3-6 carbon atoms which is attached to a linear or branched chain saturated hydrocarbon group having 1-6 carbon atoms; wherein one or more carbon atoms are substituted by one or more halogens. 
 
     
     
       2. The compound according to  claim 1 , wherein:
 R 1 , R 2  and R 3  each independently represent H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol, alkoxylalkyl, aralkyl or aryl; 
 X and Y each independently represent N atom or CH group, wherein the CH group can optionally be substituted by R 4 , and R 4  may be H, alkyl, cyano halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol, alkoxylalkyl, aralkyl or aryl; 
 Z and M each independently represent NH, O, S or CH group with the proviso that one of Z and M is NH, O or S, wherein the CH or NH group can each optionally and independently be substituted by R 5 , and R 5  may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol, alkoxylalkyl, aralkyl or aryl; 
 A 1  independently represents NH, O, S or alkylene group, wherein the NH or alkylene group can each optionally and independently be substituted by R 6 , and R 6  may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol, alkoxylalkyl, aralkyl or aryl; 
 A 2  independently represents alkylene, C(O)NH, C(O), NHC(O), alkylene-C(O), C(O)-alkylene, alkylene-C(O)-alkylene or NHC(O)NH, wherein the above groups can each optionally and independently be substituted by R 7 , and R 7  may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol, alkoxylalkyl, aralkyl or aryl; 
 Q 1  is selected from aryl and Het, wherein the aryl and Het can each optionally and independently be substituted by one or more R 8 , and R 8  may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol, alkoxylalkyl, aralkyl or aryl; 
 Q 2  is selected from aryl and Het, wherein the aryl and Het can each optionally and independently be substituted by one or more R 9 , and R 9  may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol, alkoxylalkyl, aralkyl or aryl. 
 
     
     
       3. The compound according to  claim 2 , wherein:
 R 1 , R 2  and R 3  each independently represent H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol or alkoxylalkyl; 
 X and Y each independently represent N atom or CH group, wherein the CH group can optionally be substituted by R 4 , and R 4  may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol or alkoxylalkyl; 
 Z and M each independently represent NH, O, S or CH group with the proviso that one of Z and M is NH, O or S, wherein the CH or NH group can each optionally and independently be substituted by R 5 , and R 5  may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol or alkoxylalkyl; 
 A 1  independently represents NH, O, S or alkylene group, wherein the NH or alkylene group can each optionally and independently be substituted by R 6 , and R 6  may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol or alkoxylalkyl; 
 A 2  independently represents alkylene, C(O)NH, C(O), NHC(O), alkylene-C(O), C(O)-alkylene, alkylene-C(O)-alkylene or NHC(O)NH, wherein the above groups can each optionally and independently be substituted by R 7 , and R 7  may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol or alkoxylalkyl; 
 Q 1  is selected from aryl and Het, wherein the aryl and Het can each optionally and independently be substituted by one or more R 8 , and R 8  may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol or alkoxylalkyl; 
 Q 2  is selected from aryl and Het, wherein the aryl and Het can each optionally and independently be substituted by one or more R 9 , and R 9  may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol or alkoxylalkyl. 
 
     
     
       4. The compound according to  claim 3 , wherein:
 R 1 , R 2  and R 3  each independently represent H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol or alkoxylalkyl; 
 X and Y each independently represent N atom or CH group, wherein the CH group can optionally be substituted by R 4 , and R 4  may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol or alkoxylalkyl; 
 Z and M each independently represent NH, O, S or CH group with the proviso that one of Z and M is NH, O or S, wherein the CH or NH group can each optionally and independently be substituted by R 5 , and R 5  may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol or alkoxylalkyl; 
 A 1  independently represents NH, O, S or alkylene group, wherein the NH or alkylene group can each optionally and independently be substituted by R 6 , and R 6  may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol or alkoxylalkyl; 
 A 2  independently represents alkylene, C(O)NH, C(O), NHC(O), alkylene-C(O), C(O)-alkylene, alkylene-C(O)-alkylene or NHC(O)NH, wherein the above groups can each optionally and independently be substituted by R 7 , and R 7  may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol or alkoxylalkyl; 
 Q 1  is unsubstituted or substituted aromatic ring selected from phenyl, naphthyl, pyrrolyl, furyl, thienyl, pyridyl, pyrazinyl and pyrimidinyl, and the above groups can each optionally and independently be substituted by one or more R 8 , and R 8  may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol or alkoxylalkyl; 
 Q 2  is aromatic ring selected from phenyl, naphthyl, pyrazolyl, furyl, thienyl, pyridyl, pyrazinyl, and pyrimidinyl; or C 3 -C 8  aliphatic carbonic ring; or aliphatic heterocycle ring selected from tetrahydropyrrolyl, piperidyl, morpholinyl, and methylpiperazinyl; and the above groups can each optionally and independently be substituted by one or more R 8 , and R 8  may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol or alkoxylalkyl. 
 
     
     
       5. The compound according to  claim 4 , wherein:
 R 1 , R 2  and R 3  each independently represent H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol or alkoxylalkyl; 
 X and Y each independently represent N atom or CH group, wherein the CH group can optionally be substituted by R 4 , and R 4  may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol or alkoxylalkyl; 
 Z and M each independently represent NH, O, S or CH group with the proviso that one of Z and M is NH, O or S, wherein the CH or NH group can each optionally and independently be substituted by R 5 , and R 5  may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol or alkoxylalkyl; 
 A 1  independently represents NH, O, S or alkylene group, wherein the NH or alkylene group can each optionally and independently be substituted by R 6 , and R 6  may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol or alkoxylalkyl; 
 A 2  independently represents alkylene, C(O)NH, C(O), NHC(O), alkylene-C(O), C(O)-alkylene, alkylene-C(O)-alkylene or NHC(O)NH, wherein the above groups can each optionally and independently be substituted by R 7 , and R 7  may be H, alkyl, cyano, halogen, haloalkyl, hydroxyl, thiol, alkoxyl, alkylthiol or alkoxylalkyl; 
 Q 1  is unsubstituted or substituted aromatic ring selected from phenyl, naphthyl, pyrrolyl, furyl, thienyl, pyridyl, pyrazinyl and pyrimidinyl and the substituent may be 1-2 halogen or trifluoromethyl; 
 Q 2  is aromatic ring selected from phenyl, naphthyl, pyrazolyl, furyl, thienyl, pyridyl, pyrazinyl, and pyrimidinyl; or C 3 -C 8  aliphatic carbonic ring; or aliphatic heterocycle ring selected from tetrahydropyrrolyl, piperidyl, morpholinyl, and methylpiperazinyl. 
 
     
     
       6. The compound according to  claim 5 , wherein:
 R 1 , R 2  and R 3  each independently represent H and C 1-4  alkyl; 
 X and Y each independently represent N atom or CH group; 
 Z and M each independently represent NH, O, S or CH group with the proviso that one of Z and M is NH, O or S; 
 A 1  independently represents NH, O, S or CH 2  group; 
 A 2  independently represents chainlike C 1-4  alkylene, C(O)NH, C(O) or NHC(O); 
 Q 1  is unsubstituted or substituted aromatic ring selected from phenyl, naphthyl, pyrrolyl, furyl, thienyl, pyridyl, pyrazinyl or pyrimidinyl and the substituent may be 1-2 halogen or trifluoromethyl; 
 Q 2  is aromatic ring selected from phenyl, naphthyl, pyrazolyl, furyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl; or C 3 -C 6  aliphatic carbonic ring; or aliphatic heterocycle ring selected from tetrahydropyrrolyl, piperidyl, morpholinyl, and methylpiperazinyl. 
 
     
     
       7. The compound according to  claim 6 , wherein:
 R 1 , R 2  and R 3  each independently represent H or methyl; 
 A 1  represents NH; 
 A 2  represents CH 2 ; 
 Q 1  represents phenyl; 
 Q 2  represents morpholinyl or methylpiperazinyl. 
 
     
     
       8. The compound according to  claim 1 , which is selected from:
 4-(4-thieno[2,3-d]pyrimidinylamino)-N-((4-methyl-1-piperazinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-1) 
 4-(4-thieno[2,3-d]pyrimidinylamino)-N-(4-((4-morpholinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-2) 
 4-(4-(6-methylthieno[2,3-d]pyrimidinyl)amino)-N-(4-((4-methyl-1-piperazinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-3) 
 4-(4-(6-methylthieno[2,3-d]pyrimidinyl)amino)-N-(4-((4-morpholinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-4) 
 4-(4-(5-methylthieno[2,3-d]pyrimidinyl)amino)-N-(4-((4-methyl-1-piperazinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-5) 
 4-(4-(5-methylthieno[2,3-d]pyrimidinyl)amino)-N-(4-((4-morpholinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-6) 
 4-(4-(5,6-dimethylthieno[2,3-d]pyrimidinyl)amino)-N-(4-((4-methyl-1-piperazinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-7) 
 4-(4-(5,6-dimethylthieno[2,3-d]pyrimidinyl)amino)-N-(4-((4-morpholinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-8) 
 4-(4-thieno[3,2-d]pyrimidinylamino)-N-(4-((4-methyl-1-piperazinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-9) 
 4-(4-thieno[3,2-d]pyrimidinylamino)-N-(4-((4-morpholinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-10) 
 4-(4-(7H-pyrrolo[2,3-d]pyrimidinyl)amino)-N-(4-((4-methyl-1-piperazinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-11) 
 4-(4-(7H-pyrrolo[2,3-d]pyrimidinyl)amino)-N-(4-((4-morpholinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-12) 
 4-(4-(6-methyl-7H-pyrrolo[2, 3-d]pyrimidinyl)amino)-N-(4-((4-methyl-1-piperazinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-13) 
 4-(4-(6-methyl-7H-pyrrolo[2,3-d]pyrimidinyl)amino)-N-(4-((4-morpholinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-14) 
 4-(4-(5-methyl-7H-pyrrolo[2, 3-d]pyrimidinyl)amino)-N-(4-((4-methy-1-piperazinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-15) 
 4-(4-(5-methyl-7H-pyrrolo[2,3-d]pyrimidinyl)amino)-N-(4-((4-morpholinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-16) 
 4-(4-(5H-pyrrolo[3,2-d]pyrimidinyl)amino)-N-(4-((4-methyl-1-piperazinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-17) 
 4-(4-(5H-pyrrolo[3,2-d]pyrimidinyl)amino)-N-(4-((4-morpholinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-18) 
 4-(4-(6-methyl-5H-pyrrolo[3,2-d]pyrimidinyl)amino)-N-(4-((4-methyl-1-piperazinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-19) 
 4-(4-(6-methyl-5H-pyrrolo[3,2-d]pyrimidinyl)amino)-N-(4-((4-morpholinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-20) 
 4-(4-furo[2,3-d]pyrimidinylamino)-N-(4-((4-methy-1-piperazinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-21) 
 4-(4-furo[2,3-d]pyrimidinylamino)-N-(4-((4-morpholinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-22) 
 4-(4-furo[3,2-d]pyrimidinylamino)-N-(4-((4-methyl-1-piperazinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-23) 
 4-(4-furo[3,2-d]pyrimidinylamino)-N-(4-((4-morpholinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-24) 
 4-(4-thieno[3,2-c]pyridylamino)-N-(4-((4-methyl)-1-piperazinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-25) 
 4-(4-thieno[3,2-c]pyridylamino)-N-(4-((4-morpholinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-26) 
 4-(4-(2-methylthieno[3,2-c]pyridyl)amino)-N-(4-((4-methyl-1-piperazinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-27) 
 4-(4-(2-methylthieno[3,2-c]pyridyl)amino)-N-(4-((4-morpholinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-28) 
 4-(7-thieno[2,3-c]pyridylamino)-N-(4-((4-methyl-1-piperazinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-29) 
 4-(7-thieno[2,3-c]pyridylamino)-N-(4-((4-morpholinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-30) 
 4-(7-(3-methylthieno[2, 3-c]pyridyl)amino)-N-(4-((4-methyl-1-piperazinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-31) 
 4-(7-(3-methylthieno[2,3-c]pyridyl)amino)-N-(4-((4-morpholinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-32) 
 4-(4-furo[3,2-c]pyridylamino)-N-(4-((4-methyl-1-piperazinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-33) 
 4-(4-furo[3,2-c]pyridylamino)-N-(4-((4-morpholinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-34) 
 4-(4-(2-methylfuro[3,2-c]pyridyl)amino)-N-(4-((4-methyl-1-piperazinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-35) 
 4-(4-(2-methylfuro[3,2-c]pyridyl)amino)-N-(4-((4-morpholinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-36) 
 4-(7-furo[2,3-c]pyridylamino)-N-(4-((4-methyl-1-piperazinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-37) 
 4-(7-furo[2,3-c]pyridylamino-N-(4-((4-morpholinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-38) 
 4-(7-furo[3,2-b]pyridylamino)-N-(4-((4-methyl-1-piperazinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-39) 
 4-(7-furo[3,2-b]pyridylamino)-N-(4-((4-morpholinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-40) 
 4-furo[2,3-b]pyridylamino)-N-(4-((4-methyl-1-piperazinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-41) 
 4-(4-furo[2,3-b]pyridylamino)-N-(4-((4-morpholinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-42) 
 4-(7-(1H-pyrrolo[2,3-c]pyridyl)amino)-N-(4-((4-methyl-1-piperazinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-43) 
 4-(7-(1H-pyrrolo[2,3-c]pyridyl)amino)-N-(4-((4-morpholinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-44) 
 4-(7-(2-methy-1H-pyrrolo[2,3-c]pyridyl)amino)-N-(4-((4-methyl-1-piperazinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-45) 
 4-(7-(2-methyl-1H-pyrrolo[2,3-c]pyridyl)amino)-N-(4-((4-morpholinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-46) 
 4-(4-(2-methylthieno[3,2-d]pyrimidine)ylamino)-N-(4-((4-methyl-1-piperazinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-47) and 
 4-(4-(2-methylthieno[3,2-d]pyrimidine)ylamino)-N-(4-((4-morpholinyl)methyl)phenyl)-1H-3-pyrazolecarboxamide (I-48). 
 
     
     
       9. The compound according to  claim 1  or the pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is the acid addition salt formed by the compound of formula (I) with one of the following acids; hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenyl acetic acid, amygdalic acid; and the acidic salts of inorganic base. 
     
     
       10. A pharmaceutical composition comprising the compound according to  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       11. A method for treating a clinical disease mediated by CDK2 and Aurora A in a subject in need thereof, comprising administrating the compound according to  claim 1  to the subject. 
     
     
       12. The method according to  claim 11 , wherein the disease is melanoma, liver cancer, kidney cancer, acute leukemia, non-small cell lung cancer, prostate cancer, thyroid cancer, skin cancer, colorectal cancer, pancreatic cancer, ovarian cancer, breast cancer, myelodysplastic syndrome, esophageal cancer, gastrointestinal cancer or mesothelioma. 
     
     
       13. A method for treating a clinical disease medicated by CMGC family and TK family kinases in a subject in need thereof, comprising administrating the compound according to  claim 1  to the subject. 
     
     
       14. A method for treating a clinical disease medicated by GSK3b, FLT3, KDR, VEGFR in a subject in need thereof, comprising administrating the compound according to  claim 1  to the subject. 
     
     
       15. The method according to  claim 14 , wherein the clinical disease is inflammation, virus infection, Type II diabetes mellitus or non-insulin-dependent diabetes mellitus, autoimmune disease, head trauma, stroke, epilepsy, Alzheimer's disease or motor neuron disease. 
     
     
       16. The compound according to  claim 1  for use as an antifungal agent.